The estrogen receptor-α is required and sufficient to maintain physiological glucose uptake in the mouse heart

Abstract

Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ERα and ERβ. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ERα might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the nonselective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovariectomized mice. Cardiac 18F-fluorodeoxyglucose uptake was strongly decreased in female ERα knockout mice compared with wild-type littermates. Analysis of cardiac mRNA accumulation by quantitative RT-PCR revealed an upregulation of genes involved in glycolisis and tricarboxylic acid cycle by ERα treatment. In conclusion, systemic activation of ERα is sufficient, and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardioprotective estrogen effects.

Figure 1

Panel I, Representative ¹⁸F-fluorodeoxyglucose (FDG)-small animal positron emission tomography (PET) images of sham-operated and ovariectomized mice (OVX) treated with placebo, 17β-estradiol, or 16α-LE2. A, Coronal sections and B, transversal views at the level of the papillary muscles. Cardiac FDG uptake was strongly visualized in sham-operated mice, whereas cardiac FDG uptake was significantly lower in ovariectomized animals. 17β-Estradiol and 16α-LE2 normalized cardiac FDG uptake to the level of sham-operated mice. Panel II, Representative PET images obtained from ERα knockout (ERKO) and wild-type (WT) mice. Cardiac FDG uptake was decreased in ERKO mice vs WT mice. A, Coronal and B, transversal PET views.

Figure 2

IP glucose tolerance test (IPGTT). Serum glucose levels were not different among intact mice (●) and ovariectomized animals (OVX) receiving placebo (○) or 17β-estradiol (▲) Treatment with 16α-LE2 (▵) tended to delay systemic glucose clearance without reaching significance. Data are presented as mean±SEM; n=6 to 8 per group.

Figure 3

Quantitative RT-PCR analyses of Affymetrix results. A, Slc2a1 (Glut 1); B, Sparc; C, Ppargc1; D, Ptgds. RT-PCR products for expression values were normalized against the housekeeping gene GAPDH. Data are presented as fold change regulation derived from 2^−ΔΔCt values from hormone-treated mice vs ovariectomized (OVX) mice treated with placebo; n=4 to 8 per group. *P<0.05 vs OVX placebo.